m6A RNA methylation promotes XIST-mediated transcriptional repression

By D. P. Patil, Chun-Kan Chen, Brian F. Pickering, A. Chow, Constanza Jackson, M. Guttman, Samie R. Jaffrey. 2016

1,551 citations recorded by the source corpus.

The long non-coding RNA X-inactive specific transcript (XIST) mediates the transcriptional silencing of genes on the X chromosome. Here we show that, in human cells, XIST is highly methylated with at least 78 N6-methyladenosine (m6A) residues—a reversible base modification of unknown function in long non-coding RNAs. We show that m6A formation in XIST, as well as in cellular mRNAs, is mediated by RNA-binding motif protein 15 (RBM15) and its paralogue RBM15B, which bind the m6A-methylation complex and recruit it to specific sites in RNA. This results in the methylation of adenosine nucleotides in adjacent m6A consensus motifs. Furthermore, we show that knockdown of RBM15 and RBM15B, or knockdown of methyltransferase like 3 (METTL3), an m6A methyltransferase, impairs XIST-mediated gene silencing. A systematic comparison of m6A-binding proteins shows that YTH domain containing 1 (YTHDC1) preferentially recognizes m6A residues on XIST and is required for XIST function. Additionally, artificial tethering of YTHDC1 to XIST rescues XIST-mediated silencing upon loss of m6A. These data reveal a pathway of m6A formation and recognition required for XIST-mediated transcriptional repression.

Subfields: Cancer Research, Molecular Biology

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Citations in the corpus

Zc3h13/Flacc is required for adenosine methylation by bridging the mRNA-binding factor Rbm15/Spenito to the m6A machinery component Wtap/Fl(2)d (2018, background): “Wang X, Feng J, Xue Y, GuanZ, ZhangD, Liu Z, Gong Z,WangQ, Huang J, TangC, et al. 2016b. Structural basis ofN6-adenosine methylation by the METTL3–METTL14 complex.”
The role of m6A RNA methylation in cancer metabolism (2022, background): “As a m6A reader, YTHDC1 can preferentially recognize m6A site on XIST, leading to the XIST mediated X-linked gene silence [115].”
RNA modifications modulate gene expression during development (2018, positive): “Finally, recent studies have suggested that m 6 A could directly or indirectly influence chromatin state and transcription through regulation of chromatin regulatory complexes and lncRNAs ( 65, 66 ).”
YTHDC1 mediates nuclear export of N6-methyladenosine methylated mRNAs (2017, background): “DOI: https://doi.org/10.7554/eLife.31311 9 of 28 This result is consistent with roles for the N-terminus of YTHDC1 in pre-mRNA splicing and function of the XIST non-coding RNA (Patil et al., 2016; Xiao et al., 2016).”
Dynamic transcriptomic m6A decoration: writers, erasers, readers and functions in RNA metabolism (2018, background): “Both RBM15 and RBM15B comprise three RNA recognition motif (RRM) domains, and combined analyses of iCLIP-seq data of RBM15/RBM15B and m(6)A-miCLIP-seq data revealed that RBM15/RBM15B binding sites are significantly enriched at the locations adjacent to m(6)A methylation sites.(57) This study suggest”
Opportunities and challenges in long-read sequencing data analysis (2020, background): “These modifications also have functional roles, for example, in mRNA stability [91], transcriptional repression [92], and translational efficiency [93].”
Rethinking m6A Readers, Writers, and Erasers (2017, methodology): “Depletion of m6A normally prevents XIST function; however, artificial tethering of DC1 to XIST was sufficient to restore XIST function in m6A-deficient cells (Patil et al. 2016).”
Temporal Control of Mammalian Cortical Neurogenesis by m6A Methylation (2017, positive): “In mammals, m(6)A is installed by the methyltransferase complex, which consists of Mettl3 (methyltransferaselike 3), Mettl14, Wtap (Wilms tumor 1-associated protein), KIAA1429, RBM15 (RNA-binding motif protein 15), and its paralog (RBM15B) (Patil et al., 2016), whereas its removal is mediated by the”